This grant represents the primary focus of our lab: understanding the effects of PGC-1 coactivators on vascular biology, and translating findings into clinically relevant avenues. During the current period of this grant, we have focused on mechanisms and physiological effects of the generation of new blood vessels by PGC-1s in muscle, heart, and elsewhere. We now propose to extend these studies to understanding the quality of the new vessels as well, specifically focusing on the ability of these vessels to transport fatty acids to the underlying skeletal myocytes. In type II diabetes, the accumulation of incompletely esterified fatty acids in skeletal muscle, i.e. lipotoxicity, is a proximate cause of insulin resistance. Because all blood vessels are lined with endothelial cells, fats must traverse through the endothelial barrier in order to be delivered to tissues. Remarkably, very little is known about how fats do this, and what molecules might regulate the process. We describe here the identification of a novel metabolite, regulated by PGC-1alpha, and secreted from skeletal myocytes, which signals endothelial cells to increase trans-endothelial fatty acid transport. We hypothesize that excess concentrations of this metabolite drives fatty acid uptake into myotubes, leading to inhibition of insulin signaling and glucose intolerance. We propose experiments to 1) Test the effect of this metabolite on lipotoxicity and insulin signaling in muscle, and on systemic glucose metabolism in intact animals. 2) Identify molecular mechanisms by which the metabolite modulates fatty acid handling in endothelial cells, including identifying its receptor. 3) Test if inhibition of endothelial fatty acid transport can protect from diabetes in both diet-induced and genetic murine models of diabetes. Lipid trafficking in and out of tissues is at the heart of diabetes, and yet little is known of how lipid get across the most prevalent barrier to travel: the vessel wall. The proposed work thus stands to identify a number of novel vascular targets for the treatment of diabetes and its complications.